What is the proper administration of methotrexate (MTX) for various medical conditions?

How to Administer Methotrexate

Methotrexate should be administered once weekly (not daily) at starting doses of 10-15 mg orally for most adults with rheumatoid arthritis or skin disease, with dose escalation of 5 mg every 2-4 weeks up to 20-30 mg weekly based on clinical response, and must always be accompanied by folic acid supplementation of at least 5 mg per week. 1

Critical Patient Education Before Prescribing

Before initiating methotrexate, you must explicitly explain the following to prevent potentially fatal errors:

• Weekly dosing schedule - Emphasize this is taken ONCE per week, not daily, as confusion about frequency is a common cause of fatal overdose 1
• The specific tablet strength being prescribed (2.5 mg vs 10 mg tablets) 1
• Therapeutic benefit may not appear for 3-12 weeks 1
• Absolute contraindication in pregnancy; effective contraception is mandatory 1
• Warning signs requiring urgent medical attention: fever/flu-like illness, mouth ulceration, unexplained bruising/bleeding, severe fatigue, nausea/vomiting/abdominal pain, dark urine, breathlessness, or cough 1
• Need for pneumococcal vaccine and yearly influenza vaccination 1
• Limit alcohol intake 1
• Potential drug interactions (NSAIDs, antibiotics, proton pump inhibitors) 1

Dosing and Route of Administration

Starting Dose

For healthy adults: Start at 10-15 mg orally once weekly 1

For patients with renal impairment or elderly patients: Consider lower starting doses of 2.5-5 mg weekly, or a test dose of 2.5-5 mg before full therapy 1, 2

Dose Escalation

• Increase by 5 mg every 2-4 weeks based on clinical response and tolerability 1
• Maximum dose typically 20-30 mg weekly 1
• Allow at least 4 weeks after dose adjustments to assess clinical response before further changes 2
• Initiation/titration to at least 15 mg weekly within 4-6 weeks is conditionally recommended over lower doses for rheumatoid arthritis 1

Route Selection

Oral administration is preferred initially due to ease of use and similar bioavailability at typical starting doses 1, 3

Switch to subcutaneous methotrexate if:

• Inadequate clinical response to oral therapy at maximum tolerated dose 1
• Intolerable gastrointestinal side effects (nausea, vomiting) on oral therapy 1
• When switching from oral to subcutaneous, maintain the same weekly dose rather than increasing it 1, 3

Subcutaneous administration advantages: Higher bioavailability, potentially reduced gastrointestinal toxicity, improved persistence with treatment 1, 3

Mandatory Folic Acid Supplementation

Prescribe folic acid at least 5 mg per week (can be given daily except on methotrexate day, or as a single weekly dose) 1

• This is a strong recommendation (Grade A evidence) 1
• Reduces gastrointestinal side effects, hepatic abnormalities, and potentially hematologic toxicity 1, 2
• Higher doses (up to 5 mg daily) may be needed for patients with persistent nausea 1, 2

Baseline Assessment Requirements

Before initiating methotrexate, obtain:

• Complete blood count (CBC) 1
• Liver function tests (ALT, AST, albumin) 1
• Renal function (creatinine, eGFR) 1
• Chest X-ray (if obtained within previous year) 1
• Consider: hepatitis B/C serology, HIV serology, varicella zoster serology (if no history of chickenpox), fasting glucose, lipid profile, pregnancy test 1
• For psoriasis patients: serum PIIINP (peptide of procollagen III) 1

Monitoring Schedule

Initial Phase (First Month)

• CBC, liver function tests, and renal function every 7-14 days 1

Maintenance Phase (After Stabilization)

• CBC, liver function tests, and renal function every 2-3 months 1
• For psoriasis patients: PIIINP at least every 3 months 1
• Clinical assessment for side effects and risk factors at each visit 1

Liver Toxicity Monitoring

Stop methotrexate if:

• Confirmed ALT/AST increase >3 times upper limit of normal 1
• May reinstitute at lower dose after normalization 1

For psoriasis patients, refer for specialist assessment if:

• PIIINP >8 mg/L on two occasions, OR
• Three measurements >4.2 mg/L in 12 months, OR

• 10 mg/L on one occasion 1

Routine liver biopsy is NOT recommended for monitoring 1

Renal Function Adjustments

Critical dosing modifications based on creatinine clearance:

• >50 mL/min: Normal dose 1
• 20-50 mL/min: Reduce dose by 50% 1
• <20 mL/min: Avoid methotrexate entirely 1
• Dialysis patients: Contraindicated 1

Myelosuppression risk increases significantly with renal dysfunction and is the most important cause of methotrexate-associated death 1

Managing Inadequate Response

If minimal efficacy after 12-16 weeks at maximum tolerated dose:

1. First: Switch to subcutaneous administration at the same weekly dose 1
2. Second: If still inadequate, consider alternative medication or combination therapy 1

Managing Intolerance

For oral methotrexate intolerance (especially nausea):

1. Split the weekly dose over 24 hours (e.g., half dose, then remaining half 12 hours later) 1
2. Switch to subcutaneous administration 1
3. Increase folic acid dose up to 5 mg daily 1
4. Take medication before bedtime or with food 1
5. Consider ondansetron 8 mg given 2 hours before methotrexate dose, repeated at 12 and 24 hours if needed 1

Perioperative Management

For elective orthopedic surgery: Methotrexate can be safely continued perioperatively without increased infection risk 1, 4, 2

For major surgery with comorbidities (e.g., diabetes): Decision to continue must be individualized, weighing disease flare risk against potential infection complications 1, 4

Inpatient Management

Temporarily discontinue methotrexate during hospitalization if:

• Acute infection requiring antibiotics 4
• Abnormal liver function (transaminases >2x upper limit of normal) 4
• Bone marrow suppression (WBC <3.5×10⁹/L or neutrophils <2×10⁹/L) 4
• Patient receiving interacting medications (NSAIDs, certain antibiotics) 4

Resume after discharge when:

• Acute illness resolved
• Liver function normalized
• Blood counts adequate
• Interacting medications discontinued 4

Absolute Contraindications

• Pregnancy or breastfeeding 1, 4
• Planning pregnancy within 3 months (both men and women) 1, 4
• Active hepatitis B infection 1
• Creatinine clearance <20 mL/min or dialysis 1
• Significant hepatic damage, severe anemia, leukopenia, or thrombocytopenia 2
• Patients unable to comply with regular blood monitoring 1

Common Pitfalls to Avoid

Daily dosing error: The most dangerous error is prescribing or taking methotrexate daily instead of weekly - this can be fatal 1. Always write "ONCE WEEKLY" in capital letters on prescriptions.

Tablet strength confusion: Both 2.5 mg and 10 mg tablets are small and similar in appearance. Prescribe only one strength (preferably 2.5 mg) and write dose in full uppercase letters 1

Inadequate folic acid: Failure to prescribe folic acid supplementation increases toxicity without improving efficacy 1

Premature discontinuation: Therapeutic benefit may take 3-12 weeks to manifest; continue for at least 12-16 weeks before declaring treatment failure 1, 2

Ignoring renal function: Failure to adjust dose for renal impairment significantly increases risk of fatal myelosuppression 1

Drug interactions: NSAIDs, trimethoprim, penicillins, and proton pump inhibitors can increase methotrexate toxicity 1